Background: People with schizophrenia misinterpret the environment, leading to inappropriate assignment[unreadable] of meaning to irrelevant stimuli and inability to recognize relevant social cues. Although the process of[unreadable] assigning meaning is beyond our understanding, the ability to detect change can be reduced to a series of[unreadable] sequential operations including 1) registration of sensory input; 2) encoding of qualitative features 3) echoic[unreadable] stimulus memory; 4) comparison of sequential inputs and 5) deviance determination. These operations are[unreadable] abnormal in schizophrenia as measured with electrophysiological responses using auditory event related[unreadable] potentials (ERPs). Central Hypothesis: The inability to form normal ERPs in schizophrenia reflects an[unreadable] inability to relay basic sensory input from the external world with high fidelity. This reduction of accurate[unreadable] sensory input leads to misinterpretation and inability to process information for learning, memory and[unreadable] executive function. Therefore, understanding the basic neurobiology of impaired sensory encoding using[unreadable] mouse ERPs will inform treatments for cognitive deficits in schizophrenia. Research Project: We previously[unreadable] demonstrated mouse analogues of the human P50, N100, mismatch negativity (MMN) and P3a. Mice that[unreadable] express a constitutively active Gsa G-protein subunit have reduced amplitude of the mouse N100 analogue,[unreadable] similar to schizophrenia. However, the role of the Gsa mutation in deviance detection is not known.[unreadable] Additionally, NMDA receptor antagonists disrupt MMN in mice, recreating the schizophrenia endophenotype.[unreadable] Also, mice with reduced expression of the presynaptic glutamate related protein dysbindin, which is linked to[unreadable] schizophrenia by post-mortem and genetic analyses, display altered electrophysiology in hippocampal slice[unreadable] preparations. However, the role of dysbindin in deviance detection is not known. The proposed project will[unreadable] determine roles of Gsa and dysbindin expression in deviance related ERPs and use these models to[unreadable] investigate novel schizophrenia treatments. Aim 1 will determine the extent to which alterations in Gsa and[unreadable] dysbindin expression disrupt deviance related ERPs, Aim 2 will determine the extent to which these[unreadable] mutations alter auditory evoked gamma oscillations and Aim 3 will determine the extent to which they alter[unreadable] auditory induced theta oscillations in mice. Environment: Studies will be performed in the laboratory of[unreadable] Steven Siegel and will be integrated with animal and human studies in the proposed Conte Center. This[unreadable] laboratory has the expertise and experience to perform all proposed studies. Future Directions: Completion[unreadable] of proposed work will further understanding of the roles of dysbindin polymorphisms and dysregulation of[unreadable] intracellular cAMP signal transduction in sensory perception in schizophrenia. Future studies will incorporate[unreadable] behavioral tasks to clarify the ways in which abnormal sensory ERPs contribute to complex cognitive deficits.[unreadable]